The CFTR NM_000492.4:c.3909C>G (NP_000483.3:p.(Asn1303Lys)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: N1303K mature CFTR was 0.5% of normal and baseline chloride transport was 0.0% of normal in a controlled variant-specific assay. Based on available guidelines, this variant is considered to be Likely Pathogenic. This variant is considered to be Pathogenic by the VCEP (CFTR2; ClinVar ID 7136).
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.CFTR encodes an ATP-binding cassette family protein that functions as a chloride channel, helping regulate salt and water movement across epithelial tissues. Disruption of CFTR causes cystic fibrosis, an inherited disorder affecting the lungs, digestive system, and other organs; CFTR has no established primary role in cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: N1303K mature CFTR was 0.5% of normal and baseline chloride transport was 0.0% of normal in a controlled variant-specific assay.
Met: p.Asn1303Lys lies in CFTR NBD2, where mature CFTR was 0.5% and baseline chloride transport 0.0% of normal.
Met at moderate strength: missense REVEL score 0.83 meets the supplied PP3 threshold of >=0.773.
Met at supporting strength: ClinVar's exact-variant CFTR2 expert panel classification is Pathogenic, satisfying the qualifying PP5 source requirement.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 (strong) plus PM1 and PP3 (moderate) satisfy the generic ACMG/AMP fallback rule, with PP5 (supporting) also applied.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 252 / 1,598,060 alleles. Recorded AF 0.000157691. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.00013884; MAF= 0.01388%, 39/280898 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000582072; MAF= 0.05821%, 6/10308 alleles, homozygotes = 0); grpmax FAF= 0.00012449.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.830. Refer to the recorded PP3/BP4 rationale for interpretation.
42 Pathogenic · 1 pathogenic · 1 Uncertain significance. ClinVar API review status: practice guideline.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 7 not met · 13 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PM1 is met because p.Asn1303Lys lies in functionally critical CFTR NBD2 and variant-specific testing shows severely impaired maturation and chloride transport.
PS1 and PM5 remain not assessed because the supplied evidence does not document the required distinct same-amino-acid or same-residue pathogenic comparator.
PP2 and BP1 remain not assessed because the supplied evidence lacks the gene-wide missense and truncating-variant distributions required by their generic definitions.
The variant-specific controlled assay provides strong functional evidence for a damaging effect on CFTR maturation and chloride-channel activity, supporting PS3.
The same assay demonstrates damage rather than preserved function, so BS3 is not met.
PS4 was not assessed because the available variant-specific case report does not provide the complete case and control denominators required to calculate OR/RR and its 95% CI.
PP4 and BP5 were not assessed because the case-specific phenotype, family history, and alternate molecular diagnosis are not documented.
PP5 was met at supporting strength from the exact-variant ClinVar CFTR2 expert-panel Pathogenic classification; BP6 was not met because that expert-panel classification is not benign.
Generic ACMG/AMP rules govern because no VCEP covers CFTR in this case.
Both criteria were evaluated on the single missense REVEL path; SpliceAI and BayesDel were not used for these missense criteria.
No criteria match.
PS3 is met at strong strength. A variant-specific in vitro study in stable Fischer rat thyroid cells expressing CFTR p.(N1303K) used normal CFTR controls, immunoblotting for maturation, and Ussing-chamber electrophysiology for chloride transport. Mature CFTR was 0.5 ± 0.3% of normal, baseline chloride transport was 0.0 ± 0.0% of normal, and ivacaftor-treated transport was only 0.8 ± 0.2% of normal with no statistically significant rescue. These quantitative results directly demonstrate a damaging effect on CFTR protein maturation and channel function and satisfy the generic PS3 definition; no additional calibration threshold was supplied in the governing rules.
PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
p.Asn1303Lys lies in CFTR nucleotide-binding domain 2 (NBD2), a functionally critical region. Variant-specific evidence identifies N1303K as an NBD2 mutant and reports mature CFTR at 0.5 ± 0.3% of normal and baseline chloride transport at 0.0 ± 0.0% of normal. The supplied population evidence shows the variant is rare in gnomAD v4.1 (AF 0.000157691; no homozygotes), while COSMIC and cancer-hotspot searches are negative; no supplied evidence establishes benign variation that would negate the critical-domain route.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
NM_000492.4:c.3909C>G is a missense variant, NP_000483.3:p.(Asn1303Lys), so the governing generic rule selects the missense REVEL path only. REVEL is 0.83, which meets the supplied PP3 moderate threshold of >= 0.773 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for PP3 because it is the wrong predictor path for a missense variant, and BayesDel is not used because no generic ACMG-strength calibration is established. The single applicable calibrated predictor supports PP3 at moderate strength without double-counting computational evidence.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Expert panel CFTR2 classified as Pathogenic.
PP5: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
PM2 is not met under the supplied generic SVI threshold. The variant is present in both population datasets, and the relevant filtering grpmax FAF is 0.00012449 in gnomAD v2.1 and 0.00015542 in gnomAD v4.1. Both exceed the PM2 supporting threshold of <=0.0001, so the allele is not absent or rare enough for PM2 under this case's generic rule.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
BA1 is not met. The required filtering frequency is the gnomAD grpmax FAF, not the popmax point estimate: gnomAD v2.1 reports grpmax FAF=0.00012449 (0.012449%) and gnomAD v4.1 reports grpmax FAF=0.00015542 (0.015542%), both far below the generic stand-alone threshold of >=0.05 (5%). The highest observed population point estimates are also only 0.000582072 in v2.1 Ashkenazi Jewish and 0.000557 in v4.1 Middle Eastern, and their subgroup allele counts are below the 2000-observed-allele requirement for using a population frequency in this assessment. Thus the frequency does not meet BA1.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met on the available population data. The appropriate filtering frequency is gnomAD grpmax FAF: 0.00012449 in v2.1 and 0.00015542 in v4.1, both well below the generic default threshold of >=0.01 (1%). The elevated subgroup point estimates are not usable for this decision because they come from small groups below 2000 observed alleles, and no maximum-credible-frequency calculation is needed to rescue a frequency that is already far below the default BS1 threshold. The data therefore do not show an allele frequency greater than expected for the disorder under the generic rule.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS2 is not met. CFTR-associated cystic fibrosis is an autosomal recessive disorder, so this criterion requires observation of the variant in a healthy adult homozygote. gnomAD v2.1 reports 0 homozygotes among 280898 alleles and gnomAD v4.1 reports 0 homozygotes among 1598060 alleles. No qualifying homozygous healthy-adult observation is available in the cited population data.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BS3 is not met because the available variant-specific functional study does not show no damaging effect on CFTR protein function or splicing. Instead, it reports nearly absent maturation and chloride transport for N1303K relative to normal CFTR, with no significant pharmacologic rescue. The evidence therefore supports PS3 and is contrary to the benign-functional requirement of BS3.
BS3: Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
NM_000492.4:c.3909C>G is a missense variant, so the governing generic rule selects REVEL only. REVEL is 0.83, which does not meet any supplied BP4 threshold; the strongest BP4 threshold is <= 0.016 and the supporting threshold is <= 0.29. SpliceAI is not substituted because its score is not applicable to the missense PP3/BP4 path, and BayesDel is not usable because no generic ACMG-strength calibration is established. Therefore BP4 is not met.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
ClinVar contains a qualifying exact-variant expert-panel record, but it classifies NM_000492.4:c.3909C>G (p.Asn1303Lys) as Pathogenic through CFTR2, not Benign or Likely benign. No exact-variant benign expert-panel classification is present, so BP6 is not met; ordinary laboratory submissions, aggregate labels, and non-expert assertions were not used.
BP6: Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant produces p.Asn1303Lys and is established as pathogenic in ClinVar, including a CFTR2 expert-panel submission, but the supplied evidence documents only NM_000492.4:c.3909C>G. PS1 requires a previously established pathogenic variant producing the same amino-acid change with a different nucleotide change; no such distinct pathogenic substitution was documented.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PS2 cannot be assessed because the available evidence does not document a de novo occurrence in a patient with confirmed disease, confirmation of both maternity and paternity, or absence of a family history. Reports of affected individuals carrying N1303K do not establish parental origin or de novo status.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The literature packet identifies PMID:1998343 as a PS4 candidate and its abstract reports the exact N1303K variant in cystic-fibrosis-associated chromosomes. However, the available abstract does not provide a complete affected-cohort denominator or a control count/frequency. Therefore an odds ratio and 95% confidence interval cannot be computed, and the ACMG/AMP PS4 requirement of OR or RR >5.0 with a confidence interval excluding 1.0 cannot be assessed. The paper was checked against its available abstract; the classifier lead is not treated as independent evidence.
PS4: The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The case evidence identifies NM_000492.4:c.3909C>G (p.Asn1303Lys) as a CFTR variant, and the reviewed literature reports it on CF chromosomes, but no documented parental or offspring testing establishes phase with a named pathogenic CFTR variant in trans. Because the required phase and affected-proband allelic evidence are unavailable, PM3 cannot be assessed.
For recessive disorders, detected in trans with a pathogenic variant...Note: This requires testing of parents (or offspring) to determine phase.
The target residue is Asn1303, but the supplied PM5 candidate artifact contains zero same-residue candidates and explicitly states that classic PM5 comparator semantics could not be confirmed. The evidence therefore does not establish a different pathogenic missense substitution at residue 1303.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PM6 cannot be assessed because the available evidence does not document an assumed de novo occurrence or provide parental testing showing that maternity and paternity were unconfirmed. Reports of affected individuals carrying N1303K do not establish de novo status.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed because the available evidence does not document co-segregation of CFTR c.3909C>G with disease in multiple affected family members, nor provide a meiosis count or familial genotype-phenotype data. Reports of unrelated affected individuals are not segregation evidence.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The variant is missense and CFTR has established pathogenic missense variation, but the supplied evidence does not provide gene-level data demonstrating both a low rate of benign missense variation and that missense variants are a common mechanism of disease. The criterion cannot be assessed from the available quantitative evidence.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
No case-specific phenotype or family-history description is available in the supplied evidence sufficient to determine whether the patient's presentation is highly specific for a disease with a single genetic etiology. Reports associating N1303K with cystic fibrosis do not substitute for assessment of the phenotype of the case being adjudicated.
PP4: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS4 cannot be assessed because the available evidence does not identify affected family members who lack CFTR c.3909C>G, provide a pedigree, or document non-segregation. Absence of family segregation data is not evidence of lack of segregation.
Lack of segregation in affected members of a family. ... Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals.
The variant is missense, but the supplied evidence does not establish that CFTR disease is caused primarily by truncating variants rather than by a mixture of missense, splice, and truncating variants. Evidence that this particular missense variant is pathogenic does not quantify the gene-wide predominance required by BP1.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The reviewed case evidence does not document this variant in trans with a pathogenic variant in a fully penetrant dominant CFTR disorder, nor in cis with a pathogenic variant in any inheritance pattern. No individual-level phase result or co-occurring pathogenic allele is provided, so BP2 cannot be assessed.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The supplied case evidence does not document that this variant was found in a case with an alternate molecular basis for disease. No alternate pathogenic molecular diagnosis or case-level exclusion evidence is available for adjudication.
BP5: Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000492.4:c.3909C>G in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Asn1303Lys). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000492.4:c.3909C>G in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Asn1303Lys). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000492.4:c.3909C>G in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Asn1303Lys). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000492.4:c.3909C>G in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Asn1303Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in CFTR, mapped onto the exon structure of NM_000492.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Middle Eastern3 / 5,386 | 0.00056 |
| Ashkenazi Jewish16 / 29,456 | 0.00054 |
| Remaining individuals14 / 61,902 | 0.00023 |
| European (non-Finnish)205 / 1,167,148 | 0.00018 |
| Admixed American6 / 59,760 | 0.0001 |
| South Asian6 / 90,146 | 6.7e-05 |
| European (Finnish)1 / 63,938 | 1.6e-05 |
| African/African American1 / 74,692 | 1.3e-05 |
| Ashkenazi Jewish6 / 10,308 | 0.00058 |
| Remaining individuals4 / 7,168 | 0.00056 |
| European (non-Finnish)23 / 128,054 | 0.00018 |
| Admixed American5 / 35,128 | 0.00014 |
| South Asian1 / 30,292 | 3.3e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000157691; MAF= 0.01577%, 252/1598060 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000557; MAF= 0.05570%, 3/5386 alleles, homozygotes = 0); grpmax FAF= 0.00015542.
This variant is present in gnomAD v2.1 (AF= 0.00013884; MAF= 0.01388%, 39/280898 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000582072; MAF= 0.05821%, 6/10308 alleles, homozygotes = 0); grpmax FAF= 0.00012449.
Not available in gnomAD-Canada v1.0.
NM_000492.4:c.3909C>G is a missense variant, NP_000483.3:p.(Asn1303Lys), so the governing generic rule selects the missense REVEL path only. REVEL is 0.83, which meets the supplied PP3 moderate threshold of >= 0.773 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI is not used for PP3 because it is the wrong predictor path for a missense variant, and BayesDel is not used because no generic ACMG-strength calibration is established. The single applicable calibrated predictor supports PP3 at moderate strength without double-counting computational evidence.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
NM_000492.4:c.3909C>G is a missense variant, so the governing generic rule selects REVEL only. REVEL is 0.83, which does not meet any supplied BP4 threshold; the strongest BP4 threshold is <= 0.016 and the supporting threshold is <= 0.29. SpliceAI is not substituted because its score is not applicable to the missense PP3/BP4 path, and BayesDel is not usable because no generic ACMG-strength calibration is established. Therefore BP4 is not met.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000492.4:c.3909C>G in CFTR is a missense substitution predicted to produce NP_000483.3:p.(Asn1303Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for CFTR, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.83. BayesDel score = 0.144972.
9 paper records listed. 2 cited in the classification.
We believe that this is a disease-causing mutation, as it involves a nonconservative amino acid change and has only been found on CF chromosomes with a consistent haplotype background.
Location Abstract
Context Original variant report describing identification of N1303K in cystic-fibrosis-associated chromosomes and its clinical association; the supplied record provides an abstract but no complete case-control table.
N1303K 1161 0.0 ± 0.0 1.7 ± 0.3 0.0 ± 0.0 0.8 ± 0.2 NS NS
Location Table 1 and Table 2; Fig. 2B
Context Stable Fischer rat thyroid cell lines individually expressing mutant CFTR forms; CFTR maturation assessed by immunoblotting and chloride transport measured by Ussing-chamber electrophysiology after forskolin activation and acute ivacaftor addition.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.000157691; MAF= 0.01577%, 252/1598060 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000557; MAF= 0.05570%, 3/5386 alleles, homozygotes = 0); grpmax FAF= 0.00015542.
This variant is present in gnomAD v2.1 (AF= 0.00013884; MAF= 0.01388%, 39/280898 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000582072; MAF= 0.05821%, 6/10308 alleles, homozygotes = 0); grpmax FAF= 0.00012449.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (42 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by CFTR2 (expert panel). (ClinVarID = 7136)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.83. BayesDel score = 0.144972.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.